Extinction-based treatment for alcohol dependence has a strong theoretical and empirical basis, but only modest positive outcomes in clinical trials. Recent basic and human research has revealed that D-cycloserine (DCS) enhances extinction to fear cues and several lines of evidence suggest that DCS may also enhance extinction to alcohol cues. Thus, DCS may be a useful pharmacological adjunct to extinction-based treatment for AUDS. The proposed study is a proof-of-concept test of whether DCS enhances extinction to alcohol cues. Sixty-six alcohol dependent adults will be enrolled in a double-blind placebo-controlled two-group (DCS [50 mg]/placebo) between-subjects human laboratory study. Subjects will undergo an initial test of reactions to alcohol cues, two extinction sessions with acute administration of DCS or placebo, and follow-up alcohol cue reactivity tests one-week and one-month later. We hypothesize that DCS will enhance extinction to alcohol cues, as evidenced by attenuated cue-elicited craving at the second extinction session, the one-week follow- up, and the one-month follow-up. A secondary aim is to investigate whether the effects of DCS on extinction to alcohol cues translate into changes in craving in daily life. Effects of DCS on arousal and affect in response to alcohol cues will also be examined. Affirmation of the proof-of-concept that DCS enhances extinction to alcohol cues will provide the empirical basis for subsequent clinical research on whether DCS enhances extinction- based treatment. Furthermore, the proposed study will employ a translational experimental paradigm that has the potential for investigating additional medications that may enhance extinction to alcohol cues in future studies. PUBLIC HEALTH RELEVANCE: Extinction-based treatment is a promising approach for treating alcohol misuse but has demonstrated only modest positive outcomes in clinical trials. D-Cycloserine has been demonstrated to enhance extinction in animal and human research on anxiety and may also enhance extinction to alcohol cues. The proposed study will empirically test whether D-Cycloserine enhances extinction to alcohol cues toward improving extinction- based treatment for alcohol misuse.